Background: Triple-negative breast cancer (TNBC) is aggressive and has a poor prognosis. Kynurenine 3-monooxygenase (KMO), a crucial kynurenine metabolic enzyme, is involved in inflammation, immune response and tumorigenesis. We aimed to study the role of KMO in TNBC. Methods: KMO alteration and expression data from public databases were analyzed. KMO expression levels in TNBC samples were analyzed using immunohistochemistry. Knockdown of KMO in TNBC cells was achieved by RNAi and CRISPR/Cas9. KMO functions were examined by MTT, colony-forming, transwell migration/invasion, and mammosphere assays. The molecular events were analyzed by cDNA microarrays, Western blot, quantitative real-time PCR and luciferase reporter assays. Tumor growth and metastasis were detected by orthotopic xenograft and tail vein metastasis mouse models, respectively. Findings: KMO was amplified and associated with worse survival in breast cancer patients. KMO expression levels were higher in TNBC tumors compared to adjacent normal mammary tissues. In vitro ectopic KMO expression increased cell growth, colony and mammosphere formation, migration, invasion as well as mesenchymal marker expression levels in TNBC cells. In addition, KMO increased pluripotent gene expression levels and promoter activities in vitro. Mechanistically, KMO was associated with b-catenin and prevented b-catenin degradation, thereby enhancing the transcription of pluripotent genes. KMO knockdown suppressed tumor growth and the expression levels of b-catenin, CD44 and Nanog. Furthermore, mutant KMO (known with suppressed enzymatic activity) could still promote TNBC cell migration/invasion. Importantly, mice bearing CRISPR KMO-knockdown TNBC tumors showed decreased lung metastasis and prolonged survival. Interpretation: KMO regulates pluripotent genes via b-catenin and plays an oncogenic role in TNBC progression.
Herbal interactions with nifedipine/felodipine through cytochrome P450 (CYP) 3A inhibition is significant in humans. Shengmai-San (SMS), a three-herbal formula of Chinese medicine, is commonly prescribed in Asia populations for cardiovascular disorders. This study aimed to elucidate the impact of SMS on nifedipine/felodipine treatment by the findings from rat pharmacokinetic study of nifedipine to the retrospective cohort study of patients with hypertension. The 3-week SMS treatment increased the systemic exposure to nifedipine by nearly two-fold and decreased nifedipine clearance by 39% in rats. Among the ingredients of SMS component herbs, schisandrin B, schisantherin A, and methylophiopogonanone A, inhibited the nifedipine oxidation (NFO) activities of rat hepatic and intestinal microsomes, as well as human CYP3A4. Methylophiopogonanone A was identified as a time-dependent inhibitor of CYP3A4. After 1:5 propensity score matching, 4,894 patients with nifedipine/felodipine use were analyzed. In patients receiving nifedipine/felodipine, the subgroup with concurrent SMS treatment had a higher incidence of headache (92.70 per 1,000 personyears) than the subgroup without SMS treatment (51.10 per 1,000 person-years). There was a positive association between headache incidence and cumulative doses of SMS (1–60 g SMS: hazard ratio (HR): 1.39; 95% confidence interval (CI): 1.11–1.74; >60 g SMS: HR: 1.97; 95% CI: 1.62–2.39; p < 0.0001). However, patients who had higher cumulative SMS doses had a lower risk of all-cause mortality (1–60 g SMS: HR: 0.67; 95% CI: 0.47–0.94; >60 g SMS: HR: 0.54; 95% CI: 0.37–0.79; p = 0.001). Results demonstrated increased rat plasma nifedipine levels after 3-week SMS treatment and increased headache incidence should be noted in nifedipine/felodipine-treated patients with prolonged SMS administration.
Herbal medicines have been widely used for the past millennia. Traditional Chinese medicine (TCM) is a major modality in Chinese medical care and has garnered global attention owing to its pharmacological effects and multi-targeted actions. The increased incidence of sequential or concurrent use of herbs and drugs in patients forces us to consider herb–drug interactions (HDIs) in this modern era. One of the main causes of HDIs is modulation of drug metabolism, in which cytochrome P450 (CYP), UDP-glucuronosyltransferase (UGT), and transporters play primary roles. In this review, we focus on in vivo studies of HDIs, particularly in the treatment of cardiovascular disease (CVD), which is currently the leading cause of disease-related mortality worldwide. A total of 55 HDIs are summarized, and their potential underlying mechanisms are examined. The pharmacokinetic (PK) and pharmacodynamic (PD) effects of three single herbs (Danshen, Ginseng, and Ginkgo) and four compound prescriptions (Shenmai injection, Shengmai-San, Shu-Jing-Hwo-Shiee-Tang, and Wu-Chu-Yu-Tang) are discussed. Due to the complex compositions and PK/PD profiles of TCMs, the determinants of significant HDIs have been listed to further define the pros and cons of HDIs in medical care.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.